Vice President, Cancer Immunology, Genentech - Ira Mellman, Ph.D. The renaissance of immunotherapy is a revolution for cancer patients
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The renaissance of immunotherapy is a revolution for
cancer patients
Ira Mellman, Ph.D.
Vice President, Cancer Immunology, Genentech
1
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mean that Roche’s earnings or earnings per share for this year or any subsequent period will necessarily
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All mentioned trademarks are legally protected. 2
The renaissance of immunotherapy is a revolution for cancer patients
Early data suggests that anti-PD-L1/PD-1
is active across a wide range of tumor types
• Melanoma: FDA approval
• NSCLC (squamous): FDA approval, 2nd line
• Renal cell carcinoma
• Breast cancer (e.g. TNBC)
• Metastatic bladder cancer
• Head & neck cancer
• Hodgkin's lymphoma
Response rates are modest, at ~10-30%
Broad activity but most patients do not benefit from single agent therapy
Using patient data to understand cancer immunity
cycle
MPDL3280A Phase 1 Data:
Urothelial Bladder Cancer Patients Progressive Disease (PD)
Why do many patients not respond?
• No pre-existing immunity?
Stable disease (SD)
What combinations will promote PRs & CRs?
• Insufficient T cell immunity?
• Multiple negative regulators?
Monotherapy durable responses (PR/CR)
What are the drivers of single agent response?
How can PRs be enhanced to CRs?
• Insufficient T cell immunity?
• Multiple negative regulators?
The cancer immunity cycle
Immunosuppression as the rate limiting step to effective
anti-tumor immunity
α-CTLA4
(ipilumumab)
Immuno-
suppression
α-PD-L1/PD-1
(multiple)
Chen & Mellman (2013) Immunity
Combinations of immunotherapeutics
Increasing response rates by keeping cancer immunity
cycle turning
* = Genentech/Roche programs
α-VEGF-A*
α-CTLA4*
α-OX40*
α-CD27*
α-CD137
α-GITR
vaccines*
α-CD40* α-PDL1*/PD1 α-OX40* (Treg)
α-LAG-3 α-CTLA4* (Treg)
α-TIGIT* α-CSF1R*
α-KIR IDO inhibitor*
Chen & Mellman (2013) Immunity
IDO (indoleamine di-oxygenase)
Another suppressor of effector T cells
Adaptive expression of PD-L1 Adaptive expression of IDO
IDO
IFNγ-‐mediated
IFNγ-‐mediated
up-‐regulation
of
up-‐regulation
of
tumor
IDO
tumor
PD-‐L1
Inhibition
of
effector
T
cell
function
Shp-2
Shp-2
MAPK"
MAPK" PI3K
PI3K pathways"
pathways"
Georgia Hatzivassiliou, Yichin Liu
IDO mediates T cell suppression by reducing
extracellular tryptophan and increasing kynurenine
Tumor cells
Dendritic
cells Macrophages
IDO*
IFNg activates
Free tryptophan IDO expression Kynurenine
high low
ñ Uncharged arylhydrocarbon
mTOR
Tryptophanol-tRNA receptor
suppressive
GCN2 kinase cytokines
FoxP3
Promote
translation Stress response Suppress Enhance
T effectors T reg
*TDO (tryptophan dioxygenase) is a second related target to IDO
Early combination data shows promising efficacy
Phase I/II study of INCB024360 plus ipilimumab in
melanoma
Best percent change
in tumor burden
in tumor burden
Percent change
Gibney et al. ASCO 2014TIGIT
Model of TIGIT regulation of T cell responses
Tumor cell
or DC • Human and murine tumor-infiltrating
CD8+ T cells express high levels of
TIGIT
ITIM • Antibody coblockade of TIGIT and PDL1
1 Competes
with
CD226
for
PVR
elicits tumor rejection in preclinical
PVR
models
100nm 1nm
CD226 TIGIT • TIGIT selectively limits the effector
function of chronically stimulated
ITAM 2 ITIM
Disrupts
CD226
ac7va7on
3 Directly
inhibits
T
cell
in
cis
CD8+ T cells
• TIGIT interacts with CD226 in cis and
disrupts CD226 homodimerization
T cellTIGIT
TIGIT and PD-L1 combination effective in PD-L1
non-responsive model
Median Tumor Volume (mm3)
10000
40 60
+ NME1
anti-PD-L1
Tumor cell
or DC Control
Control
Median Tumor Volume (mm3)
Anti-PD-L1
anti-PD-L1
NME1
TIGIT
anti-PD-L1
Complete Remission (CR)
1000
30
NME1
ITIM
Control
Day
PVR 1 Competes
with
CD226
for
PVR
20
100nm 1nm Anti-PD-L1
anti-PD-L1
100
CD226 TIGIT + TIGIT
+ NME1
10
ITAM 2 ITIM
Disrupts
CD226
ac7va7on
3 Directly
inhibits
T
cell
in
cis
Complete Remission (CR)
0
10
10000
1000
100
10
0 10 20 30 40 60
Day
T cellOX40 function and potential in oncology
Promote antigen dependent effector T cell activation and
T regulatory cell inhibition
OX40 engagement on
Treg cells
Primary Tumor Challenge (EMT6)
OX40L
Tumor Volume (mm3)
Antigen Control
Presenting Cell 3000
Anti-mouse OX40
Treg
2000
OX40L
OX40L 1000
TCR
OX40
0
OX40 IFN-γ
0 10 20 30 40 50
day
day
Effector T Treatment
cell
Adapted from Nature Rev Immunol. 4:420 (2004).Increase in Teff cells by anti-OX40 may create need to
combine with anti-PDL1
anti-OX40
OX40L
OX40
IFN-γ"
T cell
IFNγ
PD-L1 PD-1 T cell
increase
CD8
anti-PDL1
receptor
HLA
PD-L1
Tumor
cell
Chen & Mellman (2013) Immunity Jul 25;39(1):1-10Anti-OX40 combined with anti-PDL1 in the MC38
model
2500 anti%PD%L1*
Tumor Volume (mm3)
2500
Tumor Volume (mm3)
!!!!!!!!!!!!!!!!!!!!!!!anti&OX40! control*
2000 !!!!!!!!!!!!!!!!!control! 2000
1500 1500
1000 1000
500 500
0 0
0 10 20 30 40 50 0 20 40 60
day day
2500
Tumor Volume (mm )
30000
3
PD-L1 Expression
2000 anti%OX40*+*anti%PD%L1*
20000
1500
1000
10000
500
0 0
0 20 40 60
C T
T
nu loid
C te
ye r
o
4+
8+
cy
m
day
D
D
Tu
lo
M
ra
G
Jeong Kim et al. AACR 2015Combination with Avastin
Increasing response rates by keeping cancer immunity
cycle turning
α-VEGF-A
Chen & Mellman (2013) ImmunityIncreases in CD8+ T cell infiltration and
vasculature changes with treatments in RCC
Pretreatment Post Avastin Post Avastin + aPD-L1
CD8 (T cells)
CD31 (vasculature)
Sznol et al. ASCO GU 2015
17Anti-PDL1 in combination with Avastin
Anti-VEGF combination: Combination of anti-PDL1 and Avastin
preclinical data (Ph1 data in renal cancer)
Cloudman melanoma
2000
a-PD-L1
1500 Control
a-VEGF
3
Tumor Volume, mm
1000
a-PD-L1 + a-VEGF
500
0
0 10 20 30 40 50
Day
Sznol et al. ASCO GU 2015
18Combinations with chemotherapy
Induced inflammation & antigen release may enhance
anti-PDL1 efficacy
Chemotherapy
Chen & Mellman (2013) ImmunityInflammation is necessary for response
Inflamed Non-inflamed
Can responses Can we convert these
be improved? to responsive?
Tumor phenotype by T cell staining
20-30% patients 70-80% patients
• T cells present in tumor • Lack lymphocytic infiltrates
• Chemokines present
(attract leukocytes)
Responsive to single agent Non-responsive to single
immunotherapies agent immunotherapies
20Combinations with chemotherapy extend the
benefit of anti-PDL1
Pre-clinical data
3000
oxaliplatin • Platinum chemo increases number of
Control
α-PDL1 CD8+ cells in animal models
2500
2000
• Compelling chemo+PD-L1
combination efficacy observed in
3
Tumor Volume, mm
1500
phase 1 studies
• Broad phase 3 combination program
1000
500 initiated in 1L NSCLC and TNBC
combo
0
0 6 12 16 22 29 36
Day
Dosing
Phase 1 chemo combination data to be presented at ASCO 2015Not all patients may have pre-existing immunity:
monitoring & promoting T cell responses
ImmTACs and bispecific antibodies
4
3
5
2 Recognition of cancer
6 cells by T cells
(CTLs, cancer cells)
ImmTACs
Bispecifics
1 7Recruiting T cells to cancer cells
ImmTACs and bispecific antibodies
Targeting intracellular tumor markers Targeting extracellular tumor markers
Cancer cell
Tumor
antigen
TCR
Knob into holes
full-length IgG T cell
Immune-mobilizing mTCR Against Cancer* T-cell Dependent Bispecific
*In colalboaration with ImmunocoreNot all patients may have pre-existing immunity:
monitoring & promoting T cell responses
Vaccines
4
3
5
Cancer antigen
presentation 2
(dendritic cells/APCs)
6
Vaccines:
• Endogenous
• Exogenous
1 7
Chen & Mellman (2013) ImmunityAnti-PDL1 Phase Ia: indication response
rates correlate with mutation frequency
Schumacher and Schreiber (2015) ScienceStructural analysis suggests that only some mutations
will be accessible to T cell receptors
Immunogenic Non-immunogenic
solvent-exposed mutation mutation in MHC groove
S E
M T S I V
Y
A G
E S W
N N M L
V
PàA RàM DàY
REPS1! AQLPNDVVL! Copine-1! SSPDSLHYL!
ADPGK! ASMTNRELM! H60! SSVIGVWYL!
FLU-NP! ASNENMETM!
26
Yadav et al (2014) NaturePromise for a PHC vaccine?
Immunization with antigenic peptides regresses growth of
established MC38 tumors
14-0584: mutated MHCI MC38 peptide vaccine; MC-38 14−0584:mutated
14-0584: mutated MHCI
MHCI MC38
MC38 peptide vaccine;
peptide MC−38MC-38
vaccine;
Raw and LME Fit Tumor Volume
Overlay Fits Tumor Volume
700
Raw and LME Fit Tumor Volume
1
0 2
2
4 6 Dose
● Control
01 − untreated control Control Adj ● ●
600 ●
Adj02 − d1: anti−CD40 50µg + pIC 100µg, IP injection. d10: anti−CD40
●
500
●
●
400
03
Adj+ − d1: anti−CD40 50µg + pIC 100µg + 3Xpeptide mix 100µg, IP
Peptides
300
●
●
●
●
● ●
● ●
● ●
●
●
Tumor Volume ( mm3)
200 ●
● ●
● ● ●
● ● ●
●
● ● ●
●
● ● ●
100 ●
●
● ●
● ●
●
● ●
● ● ●
●
● ●
0
3
700
Adj+peptides
600
500
● 400
Immunization
300
●
● 200
●
●
●
●
●
●
●
●
●
●
● ● 100
●
● ●
●
● ●
0
0 2 4 6
Day
Yadav et al (2014) NatureStrategic vision: lead by developing best in class
combination therapies
T cell trafficking Combinations with immunotherapies
4 aCD40 ✔
Priming & activation
Vaccines, Oncolytic Viruses ✔✔
anti-CEA-IL2v
aCTLA-4 ✔
anti-OX40
anti-CTLA4 3 aOX40 ✔
aCD27 ✔
anti-CD27*
aCEA-IL2v ✔
anti cytokine
CD38*
5 TaVEGF
cell infiltration
T Cell Bispecifics ✔
ImmTACs Planned
IDOi ✔✔
aCSF1R ✔
aTIGIT Planned
Cytokines, anti-cytokines ✔
2 Immuno- Combinations with other agents
suppression 6 aVEGF ✔
Antigen presentation Cancer T cell recognition aCD38 ✔
anti-CD40 anti-HER2-CD3 FGFR1 ✔
IMA942 vaccine* anti-CD20-CD3 EGFRi ✔✔
oncolytic viruses* ImmTAC* ALKi Planned
1 7 BRAFi ✔
Antigen release T cell killing MEKi ✔
EGFRi anti-OX40 BTKi ✔
ALKi anti-CSF-1R aCD20 ✔
BRAFi anti-CEA-IL2v aHER2 ✔
MEKi IDO inhibitor* Chemo ✔ ✔
Chemo TIGIT HDAC ✔
FGFR1* IDO1/TDO inhibitor* A2V ✔
BTKi
HDAC
Clinical development ✔ Partnered external combo
Preclinical development ✔ Internal combo
* Partnered projects
Chen & Mellman (2013) ImmunityDoing now what patients need next
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